Alternative titles; symbols
HGNC Approved Gene Symbol: GDF11
Cytogenetic location: 12q13.2 Genomic coordinates (GRCh38) : 12:55,743,122-55,757,264 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.2 | ?Vertebral hypersegmentation and orofacial anomalies | 619122 | Autosomal dominant | 3 |
Growth/differentiation factor-11 is a secreted protein factor that functions globally to regulate anterior/posterior axial patterning (McPherron et al., 1999).
McPherron et al. (1997) described a novel mouse TGF-beta family member, myostatin, encoded by the Mstn gene (601788), that has an essential role in regulating skeletal muscle mass. Using Mstn as probe in a low-stringency screen of mouse and human genomic libraries and a human spleen cDNA library, McPherron et al. (1999) cloned mouse and human GDF11. During early mouse embryogenesis, Gdf11 was expressed in the primitive streak and tail bud regions, which are sites where new mesodermal cells are generated.
By in situ hybridization of sections and whole-mount mouse embryos, Nakashima et al. (1999) found that Gdf11 was first expressed in restricted domains at 8.5 days postcoitus (dpc), with highest expression in tail bud. At 10.5 dpc, Gdf11 was expressed in branchial arches, limb bud, tail bud, and posterior dorsal neural tube. Later, it was expressed in terminally differentiated odontoblasts, nasal epithelium, retina, and specific regions of brain.
Using a bovine BMP-related sequence to design primers, Gamer et al. (1999) cloned BMP11 by PCR of a human genomic library. The deduced 407-amino acid protein has features of a BMP family member, including a signal sequence for secretion, an RxxR proteolytic processing site, and a C-terminal region with a highly conserved pattern of cysteines. Human and mouse BMP11 share 99.5% amino acid identity.
Using SDS-PAGE, Ge et al. (2005) found that the mouse Gdf11 precursor protein had an apparent molecular mass of 50 kD. Proteolytic processing of Gdf11 between gly119 and asp120 resulted in release of a 37-kD prodomain and a 12.5-kD mature Gdf11 protein.
Cox et al. (2019) analyzed Gdf11 expression in various mouse embryonic facial tissue microarray datasets and found significant expression in maxillary, mandibular, and frontonasal tissues at embryonic day 10.5. Immunohistochemical staining of human palatal tissue sections demonstrated coexpression of GDF11 and the GDF11 antagonist FST (136470) in the palatal epithelium, including the medial epithelial seam, as well as throughout the palatal and tongue mesenchyme.
Hartz (2015) mapped the GDF11 gene to chromosome 12q13.2 based on an alignment of the GDF11 sequence (GenBank AF100907) with the genomic sequence (GRCh38).
HOX proteins control many features of central nervous system development. Liu et al. (2001) found that signaling by fibroblast growth factors (see 134920), Gdf11, and retinoids established the rostrocaudal pattern of Hoxc (see 142972) expression in motor neurons in developing spinal cord of embryonic chicken.
Kim et al. (2005) demonstrated that mouse Gdf11 controls the number of retinal ganglion cells, as well as amacrine and photoreceptor cells, that form during development. Gdf11 does not affect proliferation of progenitors, a major role of Gdf11 action in other tissues, but instead controls duration of expression of Math5 (ATOH7; 609876), a gene that confers competence for retinal ganglion cell genesis, in progenitor cells. Thus, Gdf11 governs the temporal windows during which multipotent progenitors retain competence to produce distinct neural progeny.
Proteolytic processing of mouse Gdf11 results in removal of the N-terminal prodomain and activation of the C-terminal domain. Ge et al. (2005) found that the C-terminal domain of mouse Gdf11 formed a noncovalent latent complex with its cleaved prodomain. Bmp1 (112264) activated Gdf11 in transfected A204 human rhabdomyosarcoma cells, resulting in expression of a SMAD (see 601595)-responsive reporter. Overexpression of the isolated prodomain of mouse Gdf11 in A204 human rhabdomyosarcoma cells inhibited Gdf11-dependent reporter activation in a dose-dependent manner. Overexpression of mature active Gdf11 inhibited nerve growth factor (NGF; 162030)-induced neurite differentiation in rat PC12 pheochromocytoma cells. Mutation of the Gdf11 precursor that eliminated proteolytic processing by Bmp1 or Tll1 (606742) stimulated neurite differentiation. Ge et al. (2005) hypothesized that the N-terminal prodomain of GDF11 modulates GDF11 activity and neural differentiation.
GDF11 is activated by the proprotein convertase PCSK5 (600488). Tsuda et al. (2011) found that teratogenic doses of all-trans retinoic acid (ATRA), when administered to pregnant mice via gavage at embryonic day 9 (E9), inhibited Pcsk5 and Gdf11 expression in the hindgut at E12 and E18. ATRA treatment resulted in anorectal malformations, with either rectourethral or rectocloacal fistula, and short tail. Furthermore, most ATRA-treated embryos exhibited sacral malformations, tethered spinal cords, and presacral masses resembling the malformations found in caudal regression syndrome (600145).
Using transgenic mice, Li et al. (2011) found that bone-specific overexpression of Bmp11 significantly increased bone deposition in embryos and resulted in postnatal mice with increased bone mineral content and bone density, likely due to enhanced osteoblast activity. Bmp11 overexpression did not alter bone area.
Using Cor-1 mouse neural stem cells, Williams et al. (2013) found that a complex of Actriib (ACVR2B; 602730) and Alk5 (TGFBR1; 190181) functioned as a Gdf11 receptor. Via this receptor, Gdf11 activated canonical Smad2 (601366)/Smad3 (603109) signaling and altered expression of approximately 4,700 genes, including genes linked to cell cycle regulation and cytoskeletal organization, within a few hours of Gdf11 treatment. In culture, Gdf11 suppressed Cor-1 cell proliferation and migration in a scratch-wound assay. Williams et al. (2013) concluded that Gdf11 is a master regulator of neural stem cell transcription, proliferation, and migration.
In young mice, Loffredo et al. (2013) identified Gdf11 as a circulating factor that declined with age, concomitant with development of cardiac hypertrophy. Treatment of old mice to restore Gdf11 to youthful levels reversed age-related hypertrophy.
Katsimpardi et al. (2014) showed that factors found in young blood induce vascular remodeling, culminating in increased neurogenesis and improved olfactory discrimination in aging mice. They also showed that GDF11 alone can improve the cerebral vasculature and enhance neurogenesis. Katsimpardi et al. (2014) concluded that the identification of factors that slow the age-dependent deterioration of the neurogenic niche in mice may constitute the basis for new methods of treating age-related neurodegenerative and neurovascular diseases.
Parabiosis experiments indicated that impaired regeneration in aged mice is reversible by exposure to a young circulation, suggesting that young blood contains humoral 'rejuvenating' factors that can restore regenerative function (Katsimpardi et al., 2014). Sinha et al. (2014) demonstrated that the circulating protein GDF11 is a rejuvenating factor for skeletal muscle. Supplementation of systemic GDF11 levels, which normally decline with age, by heterochronic parabiosis or systemic delivery of recombinant protein, reversed functional impairments and restored genomic integrity in aged muscle stem cells. Increased GDF11 levels in aged mice also improved muscle structural and functional features and increased strength and endurance exercise capacity. Sinha et al. (2014) concluded that GDF11 systemically regulates muscle aging and may be therapeutically useful for reversing age-related skeletal muscle and stem cell dysfunction.
In 5 affected members over 3 generations of a family segregating vertebral hypersegmentation and orofacial anomalies (VHO; 619122), Cox et al. (2019) identified heterozygosity for a missense mutation in the GDF11 gene (R298Q; 603936.0001) that was not found in unaffected family members or in public variant databases. Functional analysis demonstrated that the R298Q substitution prevents cleavage to the active form of the protein, resulting in loss of function.
The bones that comprise the axial skeleton have distinct morphologic features characteristic of their positions along the anterior/posterior axis. McPherron et al. (1999) found that homozygous mutant mice carrying a targeted deletion of Gdf11 exhibited anteriorly directed homeotic transformations throughout the axial skeleton and posterior displacement of the hindlimbs. The effect of the mutation was dose dependent, as Gdf11 +/- mice had a milder phenotype than Gdf11 -/- mice. Mutant embryos showed alterations in patterns of Hox (see 142950) gene expression, suggesting that Gdf11 acts upstream of the Hox genes. McPherron et al. (1999) interpreted their findings to indicate that Gdf11 is a secreted signal that acts globally to specify positional identity along the anterior/posterior axis. To their knowledge, Gdf11 was the first secreted protein to be discovered that functions globally to regulate anterior/posterior axial patterning. The homeotic transformations observed in Gdf11 mutant mice were more extensive than those seen either by genetic manipulation of presumed patterning genes or by administration of retinoic acid. The question was raised of whether Gdf11 and retinoic acid interact to regulate Hox gene expression and anterior/posterior patterning and whether Gdf11 regulates the patterning of tissues other than those studied by McPherron et al. (1999).
Wu et al. (2003) presented evidence that mouse Gdf11 is involved in an inhibitory feedback mechanism that limits the generation of new neurons by neuronal progenitors in the olfactory epithelium. In vitro, Gdf11 inhibits neurogenesis in olfactory epithelium progenitors by inducing Kip1 (600778) and reversible cell cycle arrest. Mice lacking functional Gdf11 had more olfactory epithelium progenitors and neurons, whereas mice lacking follistatin (136470), a Gdf11 antagonist, had decreased progenitors and neurons.
Szumska et al. (2008) found that knockout of Gdf11 in mice resulted in anteroposterior patterning defects, renal and palatal agenesis, presacral mass, anorectal malformation, and exomphalos. The authors noted that this phenotype partially phenocopied a point mutation in the mouse Pcsk5a gene that inactivated Pcsk5a, rendering it unable to proteolytically process Gdf11 to its active form.
In 5 affected members of a large family (family 4527) segregating vertebral hypersegmentation and orofacial anomalies (VHO; 619122) over 3 generations, Cox et al. (2019) identified heterozygosity for a c.893G-A transition (c.893G-A, NM_005811.4) in the GDF11 gene, resulting in an arg298-to-gln (R298Q) substitution at a highly conserved residue within the RXXR motif, at which cleavage occurs. The mutation segregated fully with disease within the family and was not found in the ExAC or gnomAD databases. Functional analysis demonstrated that the R298Q substitution completely prevents cleavage by furin (136950), suggesting that the mutant GDF11 would be inactive. The R298Q mutant showed minimal ability to activate a SMAD (see 601595)-sensitive reporter compared to wildtype GDF11, confirming loss of function. In addition, transfection of both wildtype GDF11 and the R298Q mutant resulted in a signal that was significantly lower than with wildtype alone, consistent with a dominant-negative effect.
Cox, T. C., Lidral, A. C., McCoy, J. C., Liu, H., Cox, L. L., Zhu, Y., Anderson, R. D., Moreno Uribe, L. M., Anand, D., Deng, M., Richter, C. T., Nidey, N. L., and 18 others. Mutations in GDF11 and the extracellular antagonist, follistatin, as a likely cause of mendelian forms of orofacial clefting in humans. Hum. Mutat. 40: 1813-1825, 2019. [PubMed: 31215115] [Full Text: https://doi.org/10.1002/humu.23793]
Gamer, L. W., Wolfman, N. M., Celeste, A. J., Hattersley, G., Hewick, R., Rosen, V. A novel BMP expressed in developing mouse limb, spinal cord, and tail bud is a potent mesoderm inducer in Xenopus embryos. Dev. Biol. 208: 222-232, 1999. [PubMed: 10075854] [Full Text: https://doi.org/10.1006/dbio.1998.9191]
Ge, G., Hopkins, D. R., Ho, W.-B., Greenspan, D. S. GDF11 forms a bone morphogenetic protein 1-activated latent complex that can modulate nerve growth factor-induced differentiation of PC12 cells. Molec. Cell. Biol. 25: 5846-5858, 2005. [PubMed: 15988002] [Full Text: https://doi.org/10.1128/MCB.25.14.5846-5858.2005]
Hartz, P. A. Personal Communication. Baltimore, Md. 2/3/2015.
Katsimpardi, L., Litterman, N. K., Schein, P. A., Miller, C. M., Loffredo, F. S., Wojtkiewicz, G. R., Chen, J. W., Lee, R. T., Wagers, A. J., Rubin, L. L. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344: 630-634, 2014. [PubMed: 24797482] [Full Text: https://doi.org/10.1126/science.1251141]
Kim, J., Wu, H.-H., Lander, A. D., Lyons, K. M., Matzuk, M. M., Calof, A. L. GDF11 controls the timing of progenitor cell competence in developing retina. Science 308: 1927-1930, 2005. [PubMed: 15976303] [Full Text: https://doi.org/10.1126/science.1110175]
Li, Z., Zeng, F., Mitchell, A. D., Kim, Y. S., Wu, Z., Yang, J. Transgenic overexpression of bone morphogenetic protein 11 propeptide in skeleton enhances bone formation. Biochem. Biophys. Res. Commun. 416: 289-292, 2011. [PubMed: 22093826] [Full Text: https://doi.org/10.1016/j.bbrc.2011.11.019]
Liu, J.-P., Laufer, E., Jessell, T. M. Assigning the positional identity of spinal motor neurons: rostrocaudal patterning of Hox-c expression by FGFs, Gdf11, and retinoids. Neuron 32: 997-1012, 2001. [PubMed: 11754833] [Full Text: https://doi.org/10.1016/s0896-6273(01)00544-x]
Loffredo, F. S., Steinhauser, M. L., Jay, S. M., Gannon, J., Pancoast, J. R., Yalamanchi, P., Sinha, M., Dall'Osso, C., Khong, D., Shadrach, J. L., Miller, C. M., Singer, B. S., Stewart, A., Psychogios, N., Gerszten, R. E., Hartigan, A. J., Kim, M.-J., Serwold, T., Wagers, A. J., Lee, R. T. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153: 828-839, 2013. [PubMed: 23663781] [Full Text: https://doi.org/10.1016/j.cell.2013.04.015]
McPherron, A. C., Lawler, A. M., Lee, S.-J. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 387: 83-90, 1997. [PubMed: 9139826] [Full Text: https://doi.org/10.1038/387083a0]
McPherron, A. C., Lawler, A. M., Lee, S.-J. Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11. Nature Genet. 22: 260-264, 1999. [PubMed: 10391213] [Full Text: https://doi.org/10.1038/10320]
Nakashima, M., Toyono, T., Akamine, A., Joyner, A. Expression of growth/differentiation factor 11, a new member of the BMP/TGF-beta superfamily during mouse embryogenesis. Mech. Dev. 80: 185-189, 1999. [PubMed: 10072786] [Full Text: https://doi.org/10.1016/s0925-4773(98)00205-6]
Sinha, M., Jang, Y. C., Oh, J., Khong, D., Wu, E. Y., Manohar, R., Miller, C., Regalado, S. G., Loffredo, F. S., Pancoast, J. R., Hirshman, M. F., Lebowitz, J., Shadrach, J. L., Cerletti, M., Kim, M.-J., Serwold, T., Goodyear, L. J., Rosner, B., Lee, R. T., Wagers, A. J. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344: 649-652, 2014. [PubMed: 24797481] [Full Text: https://doi.org/10.1126/science.1251152]
Szumska, D., Pieles, G., Essalmani, R., Bilski, M., Mesnard, D., Kaur, K., Franklyn, A., El Omari, K., Jefferis, J., Bentham, J., Taylor, J. M., Schneider, J. E., and 16 others. VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5. Genes Dev. 22: 1465-1477, 2008. [PubMed: 18519639] [Full Text: https://doi.org/10.1101/gad.479408]
Tsuda, T., Iwai, N., Deguchi, E., Kimura, O., Ono, S., Furukawa, T., Sasaki, Y., Fumino, S., Kubota, Y. PCSK5 and GDF11 expression in the hindgut region of mouse embryos with anorectal malformations. Europ. J. Pediat. Surg. 21: 238-241, 2011. [PubMed: 21480163] [Full Text: https://doi.org/10.1055/s-0031-1273691]
Williams, G., Zentar, M. P., Gajendra, S., Sonego, M., Doherty, P., Lalli, G. Transcriptional basis for the inhibition of neural stem cell proliferation and migration by the TGF-beta-family member GDF11. PLoS One 8: e78478, 2013. [PubMed: 24244313] [Full Text: https://doi.org/10.1371/journal.pone.0078478]
Wu, H.-H., Ivkovic, S., Murray, R. C., Jaramillo, S., Lyons, K. M., Johnson, J. E., Calof, A. L. Autoregulation of neurogenesis by GDF11. Neuron 37: 197-207, 2003. [PubMed: 12546816] [Full Text: https://doi.org/10.1016/s0896-6273(02)01172-8]